Clinical Trial Results:
Lenalidomide, bendamustine and rituximab as first-line therapy for patients >65 years with mantle cell lymphoma
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Summary
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EudraCT number |
2008-007246-60 |
Trial protocol |
SE FI DK |
Global end of trial date |
12 Apr 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Jun 2021
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First version publication date |
03 Jun 2021
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Other versions |
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Summary report(s) |
Publication |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NLG-MCL4 (LENA-BERIT)
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00963534 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Lund University Hospital
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Sponsor organisation address |
Lund University Hospital, Department of Oncology, Lund, Sweden, 221 85
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Public contact |
Jan Sundberg, Lund University Hospital,
Department of Oncology,
Clinical Trial Unit, +46 46 17 70 34, jan.sundberg@skane.se
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Scientific contact |
Mats Jerkeman, Lund University Hospital,
Department of Oncology, +46 46 17 75 20, mats.jerkeman@med.lu.se
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Apr 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Apr 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Apr 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
• Phase I: Establishing maximally tolerable dose (MTD) of lenalidomide in combination with bendamustine and rituximab.
• Phase II: The primary efficacy variable was the evaluation of progression-free survival with lenalidomide, bendamustine and rituximab as frontline therapy in mantle cell
lymphoma patients.
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Protection of trial subjects |
Dose-limiting toxicity (DLT) was defined as any grade 3 to 5 non hematologic
adverse event (AE) within the first 2 cycles of lenalidomide, bendamustine and rituximab, with the
exception of thromboembolic events grade 3 to 4, nonpersisting nausea, diarrhea,
elevated transaminases, or events attributed to progressive disease. Arecovery to
absolute neutrophil count ≥ 1.0 x 109/L and platelet count ≥ 100 x 109/L was
required before the next cycle was started.
Initially, the protocol included premedication with corticosteroids before
rituximab infusion exclusively in cycle 1, but after protocol amendment corticosteroids were administered before every rituximab
infusion, and in cycle 2, all patients received oral prednisone 20 mg days 1 to 14,
followed by 1 week tapering of the dose. The use of granulocyte colonystimulating
factor was mandatory in cycles 1 to 6, because the addition of lenalidomide
was expected to augment hematologic toxicity.
Antibiotic prophylaxis was not initially recommended. After the first case of
Pneumocystis carinii pneumonia (PCP), co-trimoxazole was prescribed to all
patients.
All patients received allopurinol 300 mg per day by mouth, days 1 to 3 in
cycle 1, but not thereafter because of the risk of cutaneous reactions in
combination with bendamustine.
Thrombosis prophylaxis was recommended to all patients during the
treatment phase, unless contraindicated (aspirin 75 mg/day, or low-molecularweight
heparin to patients with a history of a thromboembolic event and/or a
known hypercoagulable state).
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Background therapy |
Prophylaxis 1. In the first cycle, all patients receive prophylactic steroid medication with 4 mg of betamethasone p o / i v (or comparable corticosteroid dose), the evening before, and one hour prior to rituximab. All patients receive prophylaxis with paracetamol 1000 mg p o and antihistamine, according to local routine, prior to rituximab in all cycles. 2. In cycle 2, all patients will receive oral prednisolone 20 mg x 2 days 1-14, then taper in one week. Corticosteroids are allowed, at the discretion of the investigator, also in the following cycles. 3. The use of G-CSF, such as inj pegfilgrastim 6 mg s c day 3, is mandatory after LBR in cycles 1-6. 4. Due to the possibility of an increased risk for Pneumocystis pneumonia, co-trimoxazole according to local guidelines, should be administered from the start of treatment until at least three months after finishing protocol therapy. 5. All patients receive allopurinol 300 mg/day p o days 1-3 cycle 1, and are encouraged to keep well hydrated during the first cycle of LBR due to potential risk of tumor lysis syndrome. Allopurinol should not be continued further due to risk of cutaneous reactions in combination with bendamustine. 6. All patients receive thrombosis prophylaxis with aspirine (acetyl salicylic acid, ASA) 75 mg/day during the treatment phase, unless contraindicated. 7. Patients with a history of a thromboembolic event and/or a known hypercoagulable state, or patients in whom ASA is contraindicated, should instead receive prophylaxis with low molecular weight heparin (LMWH), at the discretion of the investigator | ||
Evidence for comparator |
Not applicable. No comparators were used. | ||
Actual start date of recruitment |
12 Oct 2009
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Norway: 14
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Country: Number of subjects enrolled |
Sweden: 27
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Country: Number of subjects enrolled |
Denmark: 4
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Country: Number of subjects enrolled |
Finland: 5
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Worldwide total number of subjects |
50
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EEA total number of subjects |
50
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
50
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85 years and over |
0
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Recruitment
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Recruitment details |
This was a phase I- II, multicenter, open label trial. The study was divided into 2 parts; in part 1 the end point was to establish maximum tolerated dose for lenalidomide in combination with bendamustine and rituximab, while in the part 2 the main end point was evaluating progression-free survival. | ||||||||||||||
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Pre-assignment
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Screening details |
Patients were eligible if they were 65 years or ≤ 65 years but unable to tolerate high-dose chemotherapy, with a confirmed diagnosis of mantle cell lymphoma stage II to IV and World Health Organization Performance status 0-3, requiring treatment as a result of at least one of the following symptoms: bulky disease, nodal or extra nodal mass . | ||||||||||||||
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Period 1
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Period 1 title |
Treatment period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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Treatment period | ||||||||||||||
Arm description |
- | ||||||||||||||
Arm type |
Single arm trial. | ||||||||||||||
Investigational medicinal product name |
Lenalidomide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
During the phase I portion of the study, dose-limiting toxicity was defined as a grade 3 or greater non-hematologic toxicity within the first two cycles of therapy, as specified below. The phase I portion of the study follows a sequential dose escalation, '3 + 3' design.
The maximum tolerated dose was defined as the highest dose studied for which the incidence of dose limiting toxicity was less than two out of the six subjects during the first cycle of therapy.
Phase 1: Phase I: Planned dose levels of lenalidomide were 5, 10, 15, 20 and 25 mg/day during cycles 1-6. In cycles 7-13, all patients will receive an initial dose of 25 mg/day.
Phase 2: Lenalidomide was used at maximum tolerated dose level from the phase I portion during cycles 1-6. In cycles 7-13, the dose is 25 mg/day. Maximum tolerated dose was established to 10 mg.
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Investigational medicinal product name |
Bendamustine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
90 mg/m2 i v, days 1-2 (cycle 1-6). Cycle length 28 days.
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Investigational medicinal product name |
Rituximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
375 mg/m2, i v, day 1, (cycle 1-6). Cycle length 28 days.
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Baseline characteristics reporting groups
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Reporting group title |
Treatment period
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Reporting group description |
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Subject analysis sets
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Subject analysis set title |
Non treatment
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Comparison group. Did not receive treatment.
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End points reporting groups
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Reporting group title |
Treatment period
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Reporting group description |
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Subject analysis set title |
Non treatment
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Comparison group. Did not receive treatment.
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End point title |
Progression free survival [1] | ||||||||
End point description |
Progression-free survival was defined as the interval between registration
date and date of documented progression, lack of response, first relapse, or death
of any cause.Overall survival was defined as time fromregistration to death from
any cause. The Kaplan-Meier method was used to estimate survival curves for
PFS and OS. Comparison of frequency of adverse events in different groups was
based on x2 tests.
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End point type |
Primary
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End point timeframe |
During the time the patient participated in the trial. Defined as the interval between
registration date and date of documented progression or lack of response, first relapse, or death of
any cause.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Progression-free survival was defined as the interval between registration date and date of documented progression, lack of response, first relapse, or death of any cause.Overall survival was defined as time fromregistration to death from any cause. The Kaplan-Meier method was used to estimate survival curves for PFS and OS. Comparison of frequency of adverse events in different groups was based on x2 tests. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase I: Establishing maximally tolerable dose (MTD) of lenalidomide in combination with bendamustine and rituximab. [2] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Phase I: Establishing maximally tolerable dose (MTD) of lenalidomide in
combination with bendamustine and rituximab.
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: In phase 1, the treatment plan followed a sequential dose escalation according to a 3+3 design. The initial dose of LEN in cycles 1 to 6 was 5 mg, escalated by 5 mg in each step. In cycles 7 to 13, the dose of LENwas 25mg. Dose-limiting toxicity (DLT) was defined as any grade 3 to 5 nonhematologic adverse event (AE) within the first 2 cycles of LBR, with the exception of thromboembolic events grade 3 to 4, nonpersisting nausea, diarrhea, elevated transaminases, or events attributed to PD. |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
During the time the patient participated in the trial, and during the follow up period (37 months after end of treatment).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
3.0
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Reporting groups
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Reporting group title |
Treatment period
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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26 May 2009 |
Version 2: Corrections of inclusions- and exclusions criteria. |
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08 Sep 2009 |
Version 2: Modification of dose adjustments, additions of investigators. |
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14 Sep 2011 |
Version 4.1: Addition of corticosteroids. Addition of co-trimoxazole. |
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19 Apr 2012 |
Version 4.2: A change in study design in the phase 1 portion. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
